11-94478988-A-G

Variant names:

• chr11-94478988-A-G
• rs680695
• NM_005591.4:c.403-112T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005591.4(MRE11):​c.403-112T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,179,136 control chromosomes in the GnomAD database, including 54,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6998 hom., cov: 33)
  • Exomes 𝑓: 0.30 (47433 hom.)
• Consequence: MRE11 NM_005591.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.549
• Publications: 17 publications found

Genes affected

MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MRE11 Gene-Disease associations (from GenCC):

• ataxia-telangiectasia-like disorder 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• prostate cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-94478988-A-G is Benign according to our data. Variant chr11-94478988-A-G is described in ClinVar as Benign. ClinVar VariationId is 1222812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005591.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	NM_005591.4	MANE Select	c.403-112T>C		intron	N/A	NP_005582.1	P49959-1
	MRE11	NM_001440460.1		c.403-112T>C		intron	N/A	NP_001427389.1
	MRE11	NM_001440461.1		c.403-112T>C		intron	N/A	NP_001427390.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.403-112T>C		intron	N/A	ENSP00000325863.4	P49959-1
	MRE11	ENST00000323977.7	TSL:1	c.403-112T>C		intron	N/A	ENSP00000326094.3	P49959-2
	MRE11	ENST00000540013.5	TSL:1	c.403-112T>C		intron	N/A	ENSP00000440986.1	F5GXT0

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44920 AN: 152018 Hom.: 7000 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.297 AC: 305106 AN: 1027000 Hom.: 47433 AF XY: 0.300 AC XY: 156862 AN XY: 523082

African (AFR) AF: 0.199 AC: 4876 AN: 24510

American (AMR) AF: 0.416 AC: 15300 AN: 36804

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 7396 AN: 22606

East Asian (EAS) AF: 0.411 AC: 14186 AN: 34534

South Asian (SAS) AF: 0.345 AC: 24969 AN: 72272

European-Finnish (FIN) AF: 0.342 AC: 13404 AN: 39192

Middle Eastern (MID) AF: 0.339 AC: 1656 AN: 4882

European-Non Finnish (NFE) AF: 0.281 AC: 209728 AN: 746428

Other (OTH) AF: 0.297 AC: 13591 AN: 45772

GnomAD4 genome AF: 0.295 AC: 44923 AN: 152136 Hom.: 6998 Cov.: 33 AF XY: 0.301 AC XY: 22375 AN XY: 74372

African (AFR) AF: 0.206 AC: 8548 AN: 41532

American (AMR) AF: 0.385 AC: 5877 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1098 AN: 3472

East Asian (EAS) AF: 0.390 AC: 2018 AN: 5170

South Asian (SAS) AF: 0.355 AC: 1711 AN: 4824

European-Finnish (FIN) AF: 0.368 AC: 3887 AN: 10574

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20802 AN: 67972

Other (OTH) AF: 0.319 AC: 673 AN: 2110

Alfa AF: 0.297 Hom.: 2075

Bravo AF: 0.294

Asia WGS AF: 0.339 AC: 1177 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.51
PhyloP100		0.55
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs680695; hg19: chr11-94212154; COSMIC: COSV60580880; COSMIC: COSV60580880;